Kanaan Lab

 

Mechanisms of Tau Toxicity

Alzheimer's disease (AD) and other tauopathies are devastating aging-related neurodegenerative diseases. These diseases are characterized by the accumulation of abnormally modified tau proteins, which is closely linked to the observed cognitive deficits. Some of the earliest pathological changes, especially in AD, follow a "dying-back" pattern in which axons are one of the first cellular compartments to exhibit abnormal structural changes and eventually degeneration. A likely pathogenic factor contributing to axonal degeneration is the tau protein, as it is critical in maintaining axonal functions. Indeed, studies using human tissue and animal model systems suggest that tau abnormalities and axonal degeneration are interconnected components of the early degenerative sequelae of AD.

The Kanaan lab has been at the forefront of identifying mechanisms by which abnormal tau proteins can contribute to toxicity in disease. Specifically, our interests are in understanding how disease-related modifications of tau alter its structure in ways that lead to tau-mediated axonal dysfunction and degeneration.  We have primarily focused on studying mechanisms driven by pathological tau conformations, such as exposure of specific motifs and oligomerization, that lead to the activation of phosphatase and kinase pathways and impairment of axonal transport in neurons (see Tau Conformations tab). Our lab uses a multifaceted approach to address study this issue ranging from molecular biology, protein biochemistry, cell culture models, in vivo models and human tissue samples.  

If successful, this project will identify a molecular mechanism for tau-induced dysfunction/degeneration that could be targeted for disease-modifying therapeutic interventions for those living with AD or other tauopathies.

Tau Conformations in Disease

Tau is known as a protein that lacks stable structure (a member of the so-called disordered protein family) which imparts a great deal of flexibility and allows for dynamic interactions with multiple proteins. While tau does not adopt the normal stable folding that many proteins do, there has long been evidence that it can fold into certain shapes or conformations. Initially, tau conformations were identified in the context of pathological forms of the protein. The Kanaan lab is a leader in the field of tau conformations and the functional implications of different forms of tau. They identified specific conformations in which the extreme amino terminal portion of the protein becomes exposed. Abnormal exposure of this motif activates a signaling pathway that disturbs cellular functions such as axonal transport. They have identified several modifications, including specific phosphoepitopes and oligomeric species, of tau in which this conformation is adopted and subsequently cause toxicity. Additionally, this work from the Kanaan lab has potential implications for how the dynamic regulation of conformations may be critical in understanding the normal behavior of tau in neurons. Although the Kanaan lab utilizes a wide range of approaches (e.g. in vitro protein biochemistry, cell and animal models and human tissue analyses) to study tau conformation in the context of disease and normal states, our work generating and characterizing novel tau monoclonal antibodies has proven instrumental to these projects (see Tau Antibodies tab).

Ongoing work continues to advance our knowledge of tau conformations, as well as the normal and pathological implications of such forms of tau.

Tau Antibodies: Driving Research and Discovery

Tau is a microtubule-associated protein that is known for its role in several neurodegenerative disease known as tauopathies. The protein was discovered in the 70’s and shortly after was recognized as the protein composing the hallmark tangle pathologies in Alzheimer’s disease (AD). Over the years, novel monoclonal tau antibodies have played an instrumental role in driving new discoveries and giving critical insights into tau biology and pathobiology, normal tau distribution within neurons and the importance of protein modifications under physiological and pathological conditions. Our lab continues to generate novel tau antibodies to advance our understanding of tau and to uncover mechanisms driving tau toxicity. For example, our lab has developed multiple antibodies against specific pathological conformations of tau that have helped uncover mechanisms whereby disease-related forms of tau lead to axonal toxicity. Additionally, our antibody work has supported studies on tau oligomers and have helped establish that they can disrupt axonal function, synaptic activity, neurophysiology and ultimately cause toxicity in neurons. These relatively unique reagents were instrumental in demonstrating that specific tau conformations are among the first changes that occur during the evolution of tau pathology in Alzheimer’s disease and other tauopathies. More recently, the Kanaan group has begun to leverage the antibody resources to develop novel disease biomarker assays (see Disease Biomarkers tab). Thus, antibodies are much more than simple reagents. They act as a link between in vitro studies, in vivo models and human disease. Our reagents drive not only our research program, but also have a significant impact on many other national and international research groups.

The overall goal of this area in the Kanaan lab is to leverage our past experiences in making tau reagents to continue driving innovation, discovery, disease biomarkers and novel therapeutics for tauopathies.

Developing Novel Disease Biomarkers

Alzheimer’s disease (AD) and AD-related dementias have a severe impact on those affected, the healthcare system and the US economy.

The development of ultrasensitive assays such as the single molecule array (SIMOA) platform has facilitated a significant biomarker opportunity that may transform the current landscape and have a large impact on our ability to manage these diseases. The SIMOA technology allows the detection of very low levels of tau, a microtubule-associated protein that composes the hallmark pathologies of tauopathies, in plasma and other biofluids. Continued pursuit of CSF biomarkers is critical, but plasma provides an important opportunity to potentially obtain critical biomarker information through routes that are relatively non-invasive, inexpensive and easy to collect serially in large volumes. Currently, there is a critical need for developing novel tau-based assays. Our lab’s overall goal is to use our large resource of established, well-characterized monoclonal tau antibodies and newly created and characterized tau monoclonal antibodies (See Tau Antibodies tab) to develop a series of novel SIMOA assays for tau in plasma and CSF. We are developing tau assays that detect total tau by targeting specific epitopes throughout the protein. Additionally, we will develop novel tau assays that detect specific pathogenic forms of tau in plasma and CSF.

Developing such assays is critical to advance the field toward obtaining assays with high specificity, sensitivity, reproducibility and predictability for identifying tauopathies, such as AD and other ADRD tauopathies.

Funding

We are fortunate to have the funding support that allows us to pursue our fight against diseases such as Alzheimer’s disease and other dementias. Without such support the discoveries and advancements made by the Kanaan Lab would not be possible.

Current Funding:

  • NIA/NIH: R01 AG067762; Kanaan PI; Title: Tau-Mediated Regulation and Dysregulation of Protein Phosphatase 1
  • NINDS/NIH: R01 NS082730; Kanaan PI, Brady PI; Title: Tau Conformation in Tauopathies and Neuronal Function
  • NIA/NIH: R21 AG065712; Kanaan PI; Title: Development of Novel Tau-SIMOA Assays
  • NIA/NIH: P01 AG14449; Mufson PD, Counts PL, Kanaan Co-I; Title: Neurobiology of Mild Cognitive Impairment in the Elderly
  • Gibby vs Parky Research Award: Kanaan PI, Moore PI; Title: LRRK2 and Tau in Parkinson's Disease
  • NINDS/NIH: R01 NS110024; Arancio PI, Kanaan Subcontract PI; Title: The role of SUMOylation in Tau-mediated pathology
  • NINDS/NIH: R56 NS117465-01; Volpicelli-Daley PI, Kanaan Subcontract PI; Title: Alpha-synuclein aggregate induced synapse loss is a pathological event contributing to Lewy body dementias
  • NIEHS/NIH: R01ES031237; Bernstein PI, Kanaan Co-I; Title: Dieldrin-induced differential gene methylation and parkinsonian toxicity

Past Funding:

  • Alzheimer’s Assoc New Investigator Grant: NIRG-10-174461; Kanaan PI; Title: Tau-Mediated Axonal Transport Dysfunction
  • Saint Mary’s Doran Foundation: Kanaan PI; Title: Understanding tau’s role in neurodegenerative diseases
  • Jean P. Shultz Biomed Res Endowment: Kanaan PI; Title: Molecular mechanisms of tau-induced neurodegeneration
  • NINDS/NIGH: P50 NS058830; Collier PI, Kanaan Co-I; Title: Aging and Parkinson’s Disease: Models of Therapeutics and Neurologic Comorbidity
  • Michael J. Fox Foundation: Alpha-Syn RFA; Manfredsson PI, Kanaan Co-I; Title: Alpha-Synuclein Aggregation Leads to Loss of Functional Forms of the Protein and Toxicity
  • Mercy Health Saint Mary’s Doran Foundation: Lipton PI, Kanaan - Recipient of Funds Title: Enhancement of Joint Translational Neuroscience Research Programs between Saint Mary’s Healthcare and MSU’s College of Human Medicine
  • NINDS/NIH: X01 NS099361; Kanaan PI; Title: Tau in Early Parkinson’s Disease
  • BrightFocus Foundation: A2013364S; Kanaan PI; Title: Tau oligomers and their potential role in toxicity leading to Alzheimer's Disease
  • Michael J. Fox Foundation: 146962; Sortwell PI, Kanaan Co-I; Title: Optimization of Nigrostriatal Degeneration in the Rat Alpha-Synuclein PFF Model
  • Department of Defense: AZ140095; Arancio PI, Kanaan Co-I; Title: TBI-Induced Formation of Toxic Tau and Its Biochemical Similarities to Tau in AD Brains
  • NIA/NIH: R01 AG044372; Kanaan PI; Title: Tau-induced axonal degeneration in Alzheimer's disease and tauopathies
  • Secchia Family Foundation Fund: Kanaan-PI; Title: Inducers of Tau Aggregation
  • Thorek Memorial Foundation: Vega PI, Lipton PI, Kanaan Co-I; Title: A high throughput process to study interacting genetic risk factors in diseasethrough informatics and gene